Testing for polygenic effects in genome-wide association studies.
Genet Epidemiol
; 39(4): 306-16, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25847094
ABSTRACT
To confirm associations with a large number of single nucleotide polymorphisms (SNPs), each with only a small effect size, as hypothesized in the polygenic theory for schizophrenia, the International Schizophrenia Consortium (2009, Nature 460748-752) proposed a polygenic risk score (PRS) test and demonstrated its effectiveness when applied to psychiatric disorders. The basic idea of the PRS test is to use a half of the sample to select and up-weight those more likely to be associated SNPs, and then use the other half of the sample to test for aggregated effects of the selected SNPs. Intrigued by the novelty and increasing use of the PRS test, we aimed to evaluate and improve its performance for GWAS data. First, by an analysis of the PRS test, we point out its connection with the Sum test [Chapman and Whittaker, Genet Epidemiol 32560-566; Pan, Genet Epidemiol 33497-507]; given the known advantages and disadvantages of the Sum test, this connection motivated the development of several other polygenic tests, some of which may be more powerful than the PRS test under certain situations. Second, more importantly, to overcome the low statistical efficiency of the data-splitting strategy as adopted in the PRS test, we reformulate and thus modify the PRS test, obtaining several adaptive tests, which are closely related to the adaptive sum of powered score (SPU) test studied in the context of rare variant analysis [Pan et al., 2014, Genetics 1971081-1095]. We use both simulated data and a real GWAS dataset of alcohol dependence to show dramatically improved power of the new tests over the PRS test; due to its superior performance and simplicity, we recommend the whole sample-based adaptive SPU test for polygenic testing. We hope to raise the awareness of the limitations of the PRS test and potential power gain of the adaptive SPU test.
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Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
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Algoritmos
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Herança Multifatorial
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Polimorfismo de Nucleotídeo Único
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Estudo de Associação Genômica Ampla
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article